Centre de Recherches Médicales de Lambaréné, Albert Schweitzer Hospital, Lambaréné, Gabon
Institut für Tropenmedizin, Universität Tübingen, Tübingen, Germany.
Antimicrob Agents Chemother. 2019 Jan 29;63(2). doi: 10.1128/AAC.01113-18. Print 2019 Feb.
Mefloquine was evaluated as an alternative for intermittent preventive treatment of malaria in pregnancy (IPTp) due to increasing resistance against the first-line drug sulfadoxine-pyrimethamine (SP). This study determined the pharmacokinetic characteristics of the mefloquine stereoisomers and the metabolite carboxymefloquine (CMQ) when given as IPTp in pregnant women. Also, the relationship between plasma concentrations of the three analytes and cord samples was evaluated, and potential covariates influencing the pharmacokinetic properties were assessed. A population pharmacokinetic analysis was performed with 264 pregnant women from a randomized controlled trial evaluating a single and a split-dose regimen of two 15-mg/kg mefloquine doses at least 1 month apart versus SP-IPTp. Both enantiomers of mefloquine and its carboxy-metabolite (CMQ), measured in plasma and cord samples, were applied for pharmacokinetic modelling using NONMEM 7.3. Both enantiomers and CMQ were described simultaneously by two-compartment models. In the split-dose group, mefloquine bioavailability was significantly increased by 5%. CMQ induced its own metabolism significantly. Maternal and cord blood concentrations were significantly correlated ( = 0.84) at delivery. With the dosing regimens investigated, prophylactic levels are not constantly achieved. A modeling tool for simulation of the pharmacokinetics of alternative mefloquine regimens is presented. This first pharmacokinetic characterization of mefloquine IPTp indicates adequate exposure in both mefloquine regimens; however, concentrations at delivery were below previously suggested threshold levels. Our model can serve as a valuable tool for researchers and clinicians to develop and optimize alternative dosing regimens for IPTp in pregnant women.
甲氟喹因对抗疟一线药物磺胺多辛-乙胺嘧啶（SP）的耐药性不断增加，故被评估为妊娠期间间歇性预防治疗疟疾（IPTp）的替代药物。本研究旨在确定在孕妇中作为 IPTp 给药时，甲氟喹对映异构体和代谢物羧基甲氟喹（CMQ）的药代动力学特征。同时，评估了三种分析物与脐带样本之间的血浆浓度关系，并评估了影响药代动力学特性的潜在协变量。对一项随机对照试验中的 264 名孕妇进行了群体药代动力学分析，该试验评估了至少相隔 1 个月给予两次 15mg/kg 甲氟喹剂量的单剂量和分剂量方案与 SP-IPTp 的疗效。使用 NONMEM 7.3 对来自血浆和脐带样本的甲氟喹对映异构体及其羧基代谢物（CMQ）进行了药代动力学建模。采用两室模型同时描述了两种对映异构体和 CMQ。在分剂量组中，甲氟喹生物利用度显著增加了 5%。CMQ 诱导其自身代谢显著增加。分娩时母体和脐带血浓度呈显著相关性（ = 0.84）。在所研究的剂量方案中，预防性水平未持续达到。本文提出了一种用于模拟替代甲氟喹方案药代动力学的建模工具。该研究首次对 IPTp 中甲氟喹的药代动力学特征进行了描述，表明两种甲氟喹方案均有足够的暴露量；然而，分娩时的浓度低于先前建议的阈值水平。本模型可以为研究人员和临床医生提供有价值的工具，用于开发和优化 IPTp 中孕妇的替代剂量方案。
